rs563495

Variant names:

• chr6-138092473-C-T
• rs563495
• NM_022121.5:c.356-205G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022121.5(PERP):​c.356-205G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 151,986 control chromosomes in the GnomAD database, including 22,295 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (22295 hom., cov: 32)
• Consequence: PERP NM_022121.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.275
• Publications: 9 publications found

Genes affected

PERP (HGNC:17637): (p53 apoptosis effector related to PMP22) Involved in activation of cysteine-type endopeptidase activity. Predicted to be located in plasma membrane. Predicted to be active in cell-cell junction. Implicated in erythrokeratodermia variabilis and mutilating palmoplantar keratoderma with periorificial keratotic plaques. [provided by Alliance of Genome Resources, Apr 2022]

PERP Gene-Disease associations (from GenCC):

• Olmsted syndrome 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• erythrokeratodermia variabilis et progressiva 7

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• mutilating palmoplantar keratoderma with periorificial keratotic plaques

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PERP	NM_022121.5	c.356-205G>A		intron_variant	Intron 2 of 2	ENST00000421351.4	NP_071404.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PERP	ENST00000421351.4	c.356-205G>A		intron_variant	Intron 2 of 2	1	NM_022121.5	ENSP00000397157.2

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81445 AN: 151868 Hom.: 22276 Cov.: 32

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.755

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.735

Gnomad FIN AF: 0.541

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.568

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.536 AC: 81501 AN: 151986 Hom.: 22295 Cov.: 32 AF XY: 0.542 AC XY: 40293 AN XY: 74276

African (AFR) AF: 0.443 AC: 18374 AN: 41474

American (AMR) AF: 0.570 AC: 8699 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 2107 AN: 3470

East Asian (EAS) AF: 0.714 AC: 3690 AN: 5168

South Asian (SAS) AF: 0.734 AC: 3537 AN: 4816

European-Finnish (FIN) AF: 0.541 AC: 5700 AN: 10534

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.549 AC: 37326 AN: 67946

Other (OTH) AF: 0.573 AC: 1211 AN: 2112

Alfa AF: 0.549 Hom.: 14111

Bravo AF: 0.532

Asia WGS AF: 0.704 AC: 2449 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.1
DANN	Benign	0.37
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs563495; hg19: chr6-138413610;